Alzheimer?s disease (AD) manifests as a devastating age-related progressive neurodegeneration. This neurodegeneration and the concomitant loss of cognitive function plagues more than 44 million individuals worldwide. Our understanding of the molecular pathogenesis of AD remains incomplete and no therapies exist to prevent, stop, or cure the associated neurodegeneration. This marks one of the greatest unmet clinical needs of our time. Through decades of research, genome-wide association studies have identified heritable coding and non-coding mutations that lead to an increased risk of developing AD. Many of these mutations, however, remain largely under-characterized and their contribution to AD pathogenesis remains unclear. Moreover, it has become increasingly clear that an individual?s lifetime risk of developing AD is not merely governed by genetics. In addition, the epigenome, the complement of all of the chemical and physical modifications imposed on DNA that do not change the underlying sequence, is also thought to play a crucial role. This project aims to define the epigenetic (Aim 1) and genetic (Aim 2) components of AD through profiling of the open chromatin landscapes and three-dimensional chromatin interactions in brain regions and primary cell types of patients with and without AD. These characterizations will identify key AD-related regulatory elements that will be functionally validated with CRISPR interference tiling assays (Aim 3). Taken together, this project will provide an unprecedented picture of the AD epigenome, identifying novel aspects of AD pathogenesis and nominating putative avenues for therapeutic intervention. This work will be performed under the co-mentorship of Dr. Howard Chang, an expert in the application of epigenomics to disease, and Dr. Thomas Montine, a leader in brain aging and AD, at the Stanford University School of Medicine, a world-class research institution. Aims 1 and 2 will be performed predominantly during the K99 mentored phase while Aims 3 and 4 will be performed predominantly during the R00 independent phase. If funded, this award will allow me to pursue a rigorous training plan in neurobiology and age-related neurodegeneration, enabling me to expand my research in new directions, learn new techniques, and acquire the knowledge and skills to establish an independent laboratory focused on the epigenetics of AD.